Endocrinología, Diabetes y Nutrición 69 (2022) 144---148

Endocrinología, Diabetes y Nutrición

www.elsevier.es/endo

SPECIAL ARTICLE

Immunonutrition for the acute treatment of MELAS

syndrome
Elizabeth Pérez-Cruz a,∗ , Carolina González-Rivera b ,
Luz del Carmen Gabriela Valencia-Olvera b

a
Metabolic Unit and Nutritional Support, Hospital Juárez de México, Mexico City, Mexico
b
Internal Medicine, Hospital Juárez de México, Mexico City, Mexico

Received 23 December 2020; accepted 25 March 2021

Available online 29 June 2021

KEYWORDS Abstract MELAS syndrome (Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-like
MELAS syndrome; episodes) is one of the most frequent mitochondrial pathologies. Its diagnosis is based on the
Immunonutrition; classic triad of symptoms its acronym stands for and the presence of ragged red fibres. There is
Carnitine; currently no curative therapy for MELAS, and treatment focuses on managing complications that
Arginine affect specific organs and functions. However, some immunonutrients can be used as a thera-
peutic alternative in patients with MELAS. We present a scientific literature review accompanied
by the clinical case of a patient with dementia and seizures admitted to the intensive care unit.
© 2021 SEEN y SED. Published by Elsevier España, S.L.U. All rights reserved.

PALABRAS CLAVE Inmunonutrición para el tratamiento agudo del síndrome MELAS

Síndrome MELAS;
Inmunonutrición; Resumen El síndrome de encefalopatía mitocondrial, acidosis láctica y episodios similares a
Carnitina; un accidente cerebrovascular (MELAS) es una de las enfermedades mitocondriales más comunes.
Arginina El diagnóstico se basa en la existencia de las condiciones incluidas en el significado del acrón-
imo, más la presencia de fibras rojas rasgadas. No existe cura para el síndrome de MELAS, su
tratamiento se enfoca en controlar las complicaciones que afectan órganos y funciones especí-
ficas. Sin embargo, algunos inmunonutrientes se han utilizado como alternativa terapéutica en
pacientes con este síndrome. Presentamos una breve revisión de la literatura en relación con
el manejo nutricional del síndrome MELAS en un paciente con demencia y crisis convulsiva, que
fue atendido en la Unidad de Cuidados Intensivos.
© 2021 SEEN y SED. Publicado por Elsevier España, S.L.U. Todos los derechos reservados.

∗ Corresponding author.
E-mail address: pece liz@hotmail.com (E. Pérez-Cruz).

https://doi.org/10.1016/j.endinu.2021.03.004
2530-0164/© 2021 SEEN y SED. Published by Elsevier España, S.L.U. All rights reserved.
 Endocrinología, Diabetes y Nutrición 69 (2022) 144---148
Introduction
MELAS syndrome is one of the most frequent mitochon-
drial pathologies, with an incidence of 10---15 cases per
100,000 people.1,2 It is a maternally inherited neurode-
generative disease, associated with heteroplasmy, and
characterised by mitochondrial encephalomyopathy, lactic
acidosis, and stroke-like episodes.3 Despite its acronym,
it has a wide spectrum of clinical variability, including
seizures, dementia, exercise intolerance, muscle weakness,
migraine, sensorineural hearing loss, peripheral neuropathy,
recurrent vomiting and short stature.3---5 Although the mito-
chondrial structure of MELAS syndrome has been known for
more than 40 years, the genomic mutation associated with
it was not described until 1988.4
MELAS diagnosis is based on the classic triad of symp-
toms its acronym stands for and the presence of ragged red
fibres.4,5 At the molecular level, it is characterised by differ-
ent mutations in the mitochondrial DNA, the most common
of them being the m.3243A>G mutation in the MT-TL1 gene
that encodes transfer RNA.3
There is currently no curative therapy for MELAS.
Its treatment focuses on managing neurological, cog-
nitive, metabolic, musculoskeletal, gastrointestinal and
cardiopulmonary complications in affected organs. Available
options mostly involve modulating mitochondrial autophagy,
increasing mitochondrial biogenesis, and restoring the
nitric oxide (NO) production and nucleotide pools. More
recently, potential new treatments have been developed,
such as interventions modulating gene expression of the
mitochondrial genome, and solid organ and stem cell trans-
plantations.
Nutrient-enriched diets can be used to modulate
the immune system, related to inflammation and
metabolic pathways. These interventions are known as
‘‘immunonutrition’’.6 For instance, branched-chain amino
acids (BCAAs), glutamine, arginine, nucleotides, increased
␻3:␻6 ratio and antioxidants are some of the nutrients
modifying such processes. Many of them have been used
as a therapeutic alternative in patients with MELAS. We
present here the clinical case of a patient with dementia
and seizures admitted to the intensive care unit (ICU),
and describe the nutritional management of his case,
accompanied by a scientific literature review.
Case
We report the case of a 46-year-old male patient, a carpen-
ter’s assistant, with a history of type 2 diabetes mellitus
(DM2), diagnosed seven months earlier, under treatment
with sulfonylureas and biguanides. Two months before
admission to the hospital, he started experiencing tinnitus,
bilateral hearing loss and complex visual hallucinations. A
month later, he experienced loss of strength and involuntary
movement of his left lower leg, accompanied by alteration in
speech with incomplete and paraphasic sentences, anorexia
and unintentional weight loss of 5 kg. On one occasion, he
experienced loss of alertness and sphincter relaxation. The
clinical picture progressed to an inability to understand and
recognise family members, for which he was referred to the
hospital.
145
On physical examination, the patient was alert with
normal physiological respiration, but he was not able
to understand or repeat what was said to him or to
name objects. The examination of the cranial nerves and
campimetry by confrontation revealed no alterations, fun-
dus without papilledema, central primary gaze, presence of
ductions and versions, isochoric pupils, presence of consen-
sual photomotor reflex and facial symmetry; the remainder
was not assessable. Furthermore, the patient showed 3/5
muscle strength in all four extremities, without atrophy or
fasciculations, and pectoral, tricipital, patellar and bilat-
eral Achilles tendon stretch reflexes equivalent to +/++++.
Other assessments included BP: 125/75 mmHg; HR: 76 bpm;
RR: 18 rpm; temp.: 36.2 ◦ C; SaO2 : 97%; FiO2 : 21%: weight:
42 kg; height: 155 cm; BMI: 17.5 kg/m2 .
Laboratory tests reported potassium 4.8 mEq/l, sodium
132 mEq/l, glucose 251 mg/dl, leukocytes 14,400 mm3 , neu-
trophils 13,210 mm3 , lymphocytes 880 mm3 , haemoglobin
14.9 g/dl, platelets 327,000 mm3 . Arterial blood gas: pH
7.42, pCO2 19.5, pO2 86.4, SO2 95.9%, HCO3 12.6, anion gap
18.5, lactate 3.7 mmol/l, glucose 255 mg/dl. Cerebrospinal
fluid (CSF) glucose 90 mg/dl, protein 53.9 mg/dl, cells 0 mm3
and hyperlactatemia.
In the non-contrast head computed tomography (CT),
partial calcifications in the subcortical nuclei and areas of
bilateral hypodensity that resemble gliosis were observed.
Magnetic resonance imaging (MRI) revealed hypointense
lesions in T1, hyperintense lesions in T2, FLAIR (fluid-
attenuated inversion recovery) at the bilateral temporopari-
etal level, predominantly on the left, and a hyperintense
lesion in the cerebellar lobe. Based on the suspicion of
autoimmune encephalitis, treatment started with methyl-
prednisolone boluses, and VGKC antibodies were assessed:
anti-LGI1 and anti-NMDA vs. anti-CV2/CRMP5, anti-Hu and
anti-Ma2 for detecting encephalitis of paraneoplastic origin.
A brain and muscle biopsy for diagnosing MELAS was also
performed.
Two days after the examinations, the patient had focal
onset seizures that progressed to generalised tonic-clonic
seizures, without recovery of alertness, and with sig-
nificant neurological deterioration, arterial hypotension
and asystole. His condition required advanced cardiopul-
monary resuscitation and admission to the ICU. In the
ICU, he was treated with phenytoin, rapid-acting insulin,
and immunonutrition. Ultrasound of the optic nerve sheath
showed measures within the expected limits. Echocardio-
gram provided data supporting heart failure with reduced
ejection fraction (30% compensated). Diffusion-weighted
MRI control showed stroke-like lesions in the tempo-
ral, parieto-occipital regions, predominantly in the left
hemisphere, and bilateral symmetric calcifications in the
bilateral caudate nuclei (Fig. 1). A left temporal lobe biopsy
revealed brain parenchyma with neuronal loss, ischaemic
necrosis and spongiosis. Immunohistochemical data showed
CD20-negative, CD3-negative and CD68-positive microglia.
Genetic testing confirmed m.A3243G mutation in the MTTL1
gene in heteroplasmic state. Immunonutrition was started
from the first day: the patient received 19 g/day of arginine
and 136 mg/day of l-carnitine. Once the MELAS diagnosis
was confirmed, 1 g of IV l-carnitine BID was added. The
patient’s progress was favourable, and he was extubated,
and endoscopic gastrostomy was performed and he was dis-
 E. Pérez-Cruz, C. González-Rivera and L.d.C.G. Valencia-Olvera
Figure 1 Diffusion-weighted MRI control showed stroke-like lesions in the temporal, parieto-occipital regions, predominantly in
the left hemisphere.
charged to the ward, where he continued treatment. Upon
discharge from the hospital, he was treated with 200 mg of
carbamazepine TID and 1 g of l-carnitine SID.
Review
The present case study reports on a critically ill patient with
a chronic degenerative disease unknown upon admission.
We know that the mutation in MELAS impairs the assem-
bly of protein complexes in the respiratory chain, resulting
in impaired mitochondrial energy production, microvascular
angiopathy and NO deficiency, which together can impair
cerebral vasodilation.3,5 These symptoms can be exacer-
bated by a compensatory inflammatory response present in
critically ill patients.
It is relevant to mention some situations experienced by
MELAS patients in contrast to other critically ill patients.
Generally, patients in critical condition, depending on
the cause, show varying degrees of hypermetabolism and
catabolism, while in patients with MELAS in an acute neuro-
critical phase, as in this case, energy expenditure decreases.
In addition, the use of analgesic agents, muscle relaxants,
barbiturates and various sedatives further contributes to
reducing energy expenditure by 12---32%.7 Some authors have
proposed the use of low-carbohydrate or high-fat diets.
Unfortunately, the results have shown that these diets cause
progressive damage of the muscle fibres.8 Therefore, the use
of indirect calorimetry is preferred as a standard for mea-
suring energy expenditure. However, due to the cost and the
difficulty in guaranteeing the availability of the equipment,
the energy intake is often estimated at 30 kcal/kg of ideal
body weight or by using various prediction formulas such as
the Harris---Benedict equation, suggested by the European
Society of Clinical Nutrition and Metabolism, as used in this
study.9
Metabolic decompensation, experienced by MELAS
patients, can occur for different reasons. It is important to
identify the underlying cause in each patient and to moni-
tor the different degrees of catabolism, in order to choose
the best treatment and achieve an adequate balance of pro-
teins and nutrients. A safe and effective administration of
proteins at 1.0---1.5 g/kg of body weight is suggested ini-
tially, and should be gradually adjusted depending on the
catabolic state.9 Lactate levels may reflect the deteriora-
tion of microcirculation and, according to some studies,
citrulline (precursor of arginine) can be used as a biomarker
of severity in patients with MELAS.10
146
Immunonutrition plays an important role in critically ill
patients due to the beneficial results of its components.
BCAAs (leucine, isoleucine and valine) serve as a metabolic
source to supplement the needs of skeletal muscle. Glu-
tamine, a conditionally essential amino acid, serves as
a metabolic substrate for enterocytes, and reduces bac-
terial translocation and production of pro-inflammatory
cytokines.11 Meanwhile, taurine has the role of maintaining
the membrane potential and the intracellular pH, as well as
modulating apoptosis (Fig. 2).
Arginine, a conditionally essential amino acid in periods
of stress and a precursor of NO, improves the prolifer-
ation response of T cells and increases phagocytosis in
critically ill patients.12 In MELAS, the energy deficit that
stimulates mitochondrial proliferation in the smooth mus-
cle and endothelial cells leads to angiopathy with impaired
blood perfusion in the microvasculature of several organs, in
addition to a deficiency of NO.3 Oral administration of argi-
nine in patients with MELAS prevents the development of
cerebrovascular accidents and reduces the degree of sever-
ity of the disease,8,13 while intravenous administration helps
to eliminate its main symptoms, such as headache, nausea,
vomiting, loss of consciousness and visual impairment.
Some critical patients may have a carnitine deficiency.
Carnitine is an amino acid that plays a crucial role in energy
production, participates in the long-chain free fatty acid
transport into the mitochondria where ␤-oxidation takes
place, and restores intracellular acetyl-CoA groups. Thus,
its use in MELAS is well-documented.8,14,15
Nucleotides and ␻3 fatty acids are other important com-
ponents of immunonutrition in critically ill patients.11,12
Nucleotides are essential for the synthesis of RNA, DNA and
energy-transporting molecules; their decrease inhibits the
function of T cells and macrophages, increasing the risk of
sepsis.11 ␻3 fatty acids, on the other hand, are a source
of energy. They are also components of cell membranes,
aid the transport of fat-soluble vitamins, and reduce the
synthesis of eicosanoids and inflammatory cytokines, lead-
ing to fewer days of mechanical ventilation in critically ill
patients, lower prevalence of infections and shorter length
of hospital stay.16,17 Based on all of the above, in this case
study, immunonutrition was used as a therapeutic strategy
from admission to the ICU.
There are other elements of immunonutrition that we
have left for the end, because they have been used as
specific therapies for MELAS (Table 1). Since in MELAS,
energy production is dependent on anaerobic metabolic
pathways, there is an elevation of lactate and reactive
oxygen species (ROS) levels, causing cell damage and
 Endocrinología, Diabetes y Nutrición 69 (2022) 144---148

Figure 2 Cellular mechanisms of the interventions.

Table 1 Specific treatment for MELAS syndrome.

Treatment Recommended doses Effect
l-Carnitine 50---100 mg/kg/day Crucial role in energy production.
Improves ␤-oxidation, restoring the
intracellular groups of mitochondrial
acetyl-CoA.3,14
l-Arginine Acute phase: 500 mg/kg/day IV or infusion of Produces greater availability of NO, improves
10 g/m2 in 24 h for 3---5 days. vasodilation and cerebral blood flow.
Chronic phase: 150---300 mg/kg/day. Reduces the frequency and severity of
Maximum 500 mg/kg/day. stroke-like episodes.3,5
Creatine 0.1---0.15 mg/kg/day Improves muscle strength and exercise
5 g for 14 days, plus 2 g of BID for 7 days. tolerance, reduces free radical production and
regenerates ATP in muscles and brain.3,5
Coenzyme Q10 150---300 mg/day or 5---30 mg/kg/day divided in Increases production of mitochondrial ATP,
Idebenone 2 doses. prevents oxidative damage and regenerates
Maximum 3000 mg other antioxidants, such as vitamin E.
Idebenone crosses the blood-brain barrier,
having a protective role in stroke-like
episodes.5,7,18,19
␣-Lipoic acid Children: 25 mg/kg Antioxidant; increases fat-free mass and total
Adults: 50---200 mg/day body water, and reduces fat.5,9
Maximum 1200 mg/day
Thiamine 50---100 mg/day for 7 days Increases the synthesis of reducing compounds.
Maximum 300 mg/day Reduces lactic acidosis and myopathy.12
Riboflavin 50---400 mg/day Precursor of flavoprotein in complex I and II,
and cofactor in other enzymatic pathways of
␤-oxidation and Krebs cycle.5
Ascorbic acid 1000---2000 mg/day Antioxidant, acceptor of electrons released by
the ubiquinone, yielding them to complex IV.5

multi-organ dysfunction. Modulation of oxidative stress is
thus a therapeutic target.14 Antioxidants, such as ascorbic
acid and vitamin E, delay or prevent the oxidation of sub-
strates, limiting stress-induced oxidative degradation and
promoting cell survival and resistance.12
Some cofactors of the respiratory chain, such as succi-
nate, coenzyme Q10, riboflavin, and thiamine --- the latter
two, components of immunonutrition --- have been useful in
MELAS treatment.8
Once the diagnosis of MELAS was confirmed, intra-
venous l-carnitine was added to achieve therapeutic
doses. Glycaemic control was achieved with rapid- and
intermediate-acting insulin until the patient was discharged,
when a DPP-4 inhibitor was prescribed. Drug interactions

147
 E. Pérez-Cruz, C. González-Rivera and L.d.C.G. Valencia-Olvera
and their adverse effects are another aspect to consider.
Due to a history of DM2, the patient had previously received
biguanides. Thus, metformin was contraindicated in this
case, as its use, combined with biguanides, can lead to lactic
acidosis.
To conclude, there are currently limited interventions to
treat MELAS. This is the first case described in the literature
in which immunonutrition is used to treat MELAS in an acute
phase. Clinical trials on more specific and effective thera-
pies are required, but immunonutrition offers an option both
for acute hospital management, as well as a complementary
strategy in chronic outpatient management.
Conflict of interest
The authors declare they have no conflict of interest.
References
1. Koga Y, Povalko N, Inoue E, Nakamura H, Ishii A, Suzuki
Y, et al. Therapeutic regimen of l-arginine for MELAS: 9-
year, prospective, multicenter, clinical research. J Neurol.
2018;265:2861---74.
2. Wei Y, Cui L, Pen B. L-Arginine prevents stroke-like episodes
but not brain atrophy: a 20-year follow-up of a MELAS patient.
Neurol Sci. 2019;40:209---11.
3. El-Hattab AW, Almannai M, Scaglia F. Arginine and citrulline
for the treatment of MELAS syndrome. J Inborn Errors Metab
Screen. 2017;5, 2326409817697399.
4. Sproule DM, Kaufmann P. Mitochondrial encephalopathy, lactic
acidosis, and stroke-like episodes: basic concepts, clinical phe-
notype, and therapeutic management of MELAS syndrome. Ann
N Y Acad Sci. 2008;1142:133---58.
5. Rinninella E, Pizzoferrato M, Cintoni M, Servidei S, Mele MC.
Nutritional support in mitochondrial diseases: The state of the
art. Eur Rev Med Pharmacol Sci. 2018;22:4288---98.
6. Tully A, Kramer KZ, Poulakidas S. Immunonutrition and sup-
plementation: pathways, promise, and pessimism. In: Surgical
metabolism. Cham: Springer; 2020. p. 261---83.
148
7. Ikejiri Y, Mori E, Ishii K, Nishimoto K, Yasuda M, Sasaki
M. Idebenone improves cerebral mitochondrial oxidative
metabolism in a patient with MELAS. Neurology. 1996;47:583---5.
8. Yeung RO, Al Jundi M, Gubbi S, Bompu ME, Sirrs S, Tarnopolsky
M, et al. Management of mitochondrial diabetes in the era of
novel therapies. J Diabetes Compl. 2021;35:107584.
9. El-Hattab AW, Zarante AM, Almannai M, Scaglia F. Therapies for
mitochondrial diseases and current clinical trials. Mol Genet
Metab. 2017;122:1---9.
10. Kaore SN, Kaore NM. Arginine and citrulline as nutraceuticals:
efficacy and safety in diseases. Nutraceuticals Academic Press;
2021. p. 925---44.
11. Standen J, Bihari D. Immunonutrition: an update. Curr Opin Clin
Nutr Metab Care. 2000;3:149---57.
12. Wernerman J, Christopher KB, Annane D, Casaer MP, Cooper-
smith CM, Deane AM, et al. Metabolic support in the critically
ill: a consensus of 19. Crit Care. 2019;23:1---10.
13. Gorchakova NA, Zaychenko AV, Sorokopud KY. Amino acids
in cardiology, gastroenterology and neurology. News Pharm.
2020;1:76---82.
14. Hsu CC, Chuang YH, Tsai JL, Jong HJ, Shen YY, Huang HL, et al.
CPEO and carnitine deficiency overlapping in MELAS syndrome.
Acta Neurol Scand. 1995;92:252---5.
15. Kang K, Shu XL, Zhong JX, Yu TT, Lei T. Effect of l-arginine
on immune function: a meta-analysis. Asia Pacific J Clin Nutr.
2014;23:351.
16. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer
R, et al. Surviving sepsis campaign: international guidelines for
management of sepsis and septic shock: 2016. Intens Care Med.
2017;43:304---77.
17. Manzanares W, Dhaliwal R, Jurewitsch B, Stapleton RD, Jeejeeb-
hoy KN, Heyland DK. Parenteral fish oil lipid emulsions in the
critically ill: a systematic review and meta-analysis. J Parent
Enteral Nutr. 2014;38:20---8.
18. Kobayashi M, Morishita H, Sugiyama N, Yokochi K, Nakano
M, Wada Y, et al. Two cases of NADH-coenzyme Q reduc-
tase deficiency: relationship to MELAS syndrome. J Pediatr.
1987;110:223---7.
19. Ihara Y, Namba R, Kuroda S, Sato T, Shirabe T. Mitochondrial
encephalomyopathy (MELAS): pathological study and success-
ful therapy with coenzyme Q10 and idebenone. J Neurol Sci.
1989;90:263---71.